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Tired muscles make lactate as fuel not punishment

Athletic trainers and competitive athletes think of lactate as the cause of muscle fatigue, reduced performance, and pain. New research suggests that’s not the case.

In the journal Cell Metabolism, George Brooks, a professor of integrative biology at the University of California, Berkeley, reviews the history of the misunderstanding of lactate—often called lactic acid— a small molecule that plays a big role in metabolism. It is typically labeled a “waste” product produced by muscles because lactate rises to high levels in the blood during extreme exercise.

Starting in the 1970s, however, Brooks, his students, postdoctoral fellows, and staff were the first to show that lactate wasn’t waste. It was a fuel produced by muscle cells all the time and often the preferred source of energy in the body: The brain and heart both run more efficiently and more strongly when fueled by lactate than by glucose, another fuel that circulates through the blood.

“It’s a historic mistake,” Brooks says. “It was thought that lactate is made in muscles when there is not enough oxygen. It has been thought to be a fatigue agent, a metabolic waste product, a metabolic poison. But the classic mistake was to note that when a cell was under stress, there was a lot of lactate, then blame it on lactate. The proper interpretation is that lactate production is a strain response; it’s there to compensate for metabolic stress. It is the way cells push back on deficits in metabolism.”

Fuel for injury or illness

Gradually, physiologists, nutritionists, clinicians, and sports medicine practitioners are beginning to realize that high lactate levels seen in the blood during illness or after injury, such as severe head trauma, are not a problem to get rid of, but, in contrast, a key part of the body’s repair process that needs bolstering.

“After injury, adrenaline will activate the sympathetic nervous system and that will give rise to lactate production,” Brooks says. “It is like gassing up the car before a race.”

Without this added fuel, the body wouldn’t have enough energy to repair itself, and Brooks says that studies suggest that lactate supplementation during illness or after injury could speed recovery.

“The reason I wrote the review is that people in all these different disciplines are seeing different effects of lactate, and I am pulling it all together,” says Brooks. “Lactate formulations have been used for decades to fuel athletes during prolonged exertions; it’s been used widely for resuscitation after injury and to treat acidosis. Now, in clinical experiments and trials, lactate is being used to help control blood sugar after injury; to fuel the brain after brain injury; to treat inflammation and swelling; for resuscitation in pancreatitis, hepatitis, and dengue infection; to fuel the heart after myocardial infarction; and to manage sepsis.”

The ‘lactate shuttle’

Brooks discovered that normal muscle cells produce lactate all the time, and coined the term “lactate shuttle” to describe the feedback loops by which lactate is an intermediary supporting the body’s cells in many tissues and organs.

We all store energy in several forms: as glycogen, made from carbohydrates in the diet and stored in the muscles; and as fatty acids, in the form of triglycerides, stored in adipose tissue. When energy is needed, the body breaks down glycogen into lactate and glucose and adipose fat into fatty acids, all of which are distributed throughout the body through the bloodstream as general fuel. However, Brooks says, he and his lab colleagues have shown that lactate is the major fuel source.

Glucose and glycogen are metabolized through a complex series of steps that culminate in lactate. For almost a century, scientists and clinicians believed that lactate is only made when cells lack oxygen. However, using isotope tracers, first in lab animals and then in people, Brooks found that we make and use lactate all the time.

Brooks describes the lactate shuttle, in which “producer” cells make lactate and the lactate is used by “consumer” cells. In muscle tissue, for example, the white, or “fast twitch,” muscle cells convert glycogen and glucose into lactate and excrete it as fuel for neighboring red, or “slow twitch,” muscle cells, where lactate is burned in the mitochondrial reticulum to produce the energy molecule ATP that powers muscle fibers. Brooks was the first to show that the mitochondria are an interconnected network of tubes—a reticulum—like a plumbing system that reaches throughout the cell cytoplasm.

The lactate shuttle is also at work as working muscles release lactate that then fuels the beating heart and improves executive function in the brain.

“It’s like the VISA of energetics; lactate is accepted by consumer cells everywhere it goes.”

In discovering the lactate shuttle and mitochondrial reticulum, Brooks and his colleagues have revolutionized thinking about metabolic regulation in the body—not just in the body under stress, but all the time.

For decades scientists and clinicians believed that in cells, glycogen and glucose are degraded to the lactate precursor substance called pyruvate. That turned out to be wrong, since pyruvate is always converted to lactate, and in most cells lactate rapidly enters the mitochondrial reticulum and is burned. Working with lactate tracers, isolated mitochondria, cells, tissues, and intact organisms, including humans, Brooks and colleagues discovered what had been missed and, consequently, misinterpreted. More recently, others have used magnetic resonance spectroscopy (MRS) to confirm that lactate is continuously formed in muscles and other tissues under fully aerobic (oxygenated) conditions.

Brooks notes that lactate can be a problem if not used. Conditioning in sports is all about getting the body to produce a larger mitochondrial reticulum in cells to use the lactate and thus perform better.

Tellingly, when lactate is around, as during intense activity, the muscle mitochondria burn it preferentially, and even shut out glucose and fatty acid fuels. Brooks used tracers to show that both the heart muscle and the brain prefer lactate to glucose as fuel, and run more strongly on lactate. Lactate also signals fat tissue to stop breaking down fat for fuel.

“One of the important things about lactate is that it gets into the circulation and participates in inter-organ communication,” says Jen-Chywan “Wally” Wang, a UC Berkeley professor of nutritional sciences and toxicology. “Which is why it’s very important in normal metabolism and an integral part of whole-body homeostasis.”

Three roles for lactate

In his review, Brooks emphasizes three major roles for lactate in the body: It’s a major source of energy; a precursor for making more glucose in the liver, which helps support blood sugar; and a signaling molecule, circulating in the body and blood and communicating with different tissues, such as adipose tissue, and affecting the expression of genes responsible for managing stress.

How the ‘building blocks’ of muscles work together

For example, studies have shown that lactate increases the production of Brain-Derived Neurotropic Factor (BDNF), which in turn, supports neuron production in the brain. And, as a fuel source, lactate immediately improves the brain’s executive function, whether lactate is infused or comes from exercise.

“It’s like the VISA of energetics; lactate is accepted by consumer cells everywhere it goes,” he says.

The fact that lactate is an all-purpose fuel makes it a problem in cancer, however, and some scientists are looking for ways to block the lactate shuttles in cancer cells to cut off their energy supplies.

“Recognition that lactate shuttles among producer and consumer cells in tumors offers the exciting possibility of reducing carcinogenesis and tumor size by blocking producer and recipient arms of lactate shuttles within and among tumor cells,” he writes in his review.

All this presages a turnaround in the appreciation of lactate, though Brooks admits that textbooks—except for his own, Exercise Physiology: Human Bioenergetics and Its Applications, now in its fourth edition—still portray lactate as a bad actor.

“Lactate is the key to what is happening with metabolism,” Brooks says. “That is the revolution.”

Source: UC Berkeley

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